Depression is a debilitating disorder that affects millions of people worldwide (Lopez A D and Murray C, 1998) and imposes a significant cost upon society (Gumnick and Nemeroff, 2000). It is a common psychiatric disorder with a lifetime prevalence of 10-20% (Wong and Lucinio, 2001). Recurrent symptoms are common, with more than 50% of patients experiencing more than one depressive episode. Depression is widespread in patients with co-existing illness, such as diabetes, cancer and stroke, and is particularly prevalent after experiencing heart attack. There are multiple symptoms of depression, including mood alteration, loss of appetite and fatigue; often the sufferer's day to day life is disrupted by lack of concentration, disturbed sleep and feelings of worthlessness. In the most severe cases, patients experience psychotic symptoms such as hallucinations, delusions, morbid and even suicidal thoughts.
Stress has been implicated as a key factor in the pathophysiology of depression and related psychiatric disorders (Caspi et al., 2003). Abnormalities in the hypothalamic pituitary adrenal (HPA) axis stress response (Heuser, 1998) and the reduced ability of the hippocampus to inhibit the HPA axis has been demonstrated in depressed patients (Heuser, 1998; Young et al., 1991). Structural changes of the hippocampus show a decrease in hippocampal volume in patients with depression and also those suffering from post-traumatic stress disorder (Sheline et al., 1996; Sapolsky, 1996; Bremner et al., 1995). Likewise, chronic stress (for example, restraint or systemic administration of glucocorticoids) results in atrophy of the vulnerable neurones in the hippocampus in rats and non-human primates (Watanabe et al., 1982; Saplosky et al., 1985; Uno et al., 1989; Sapolsky et al., 1990; Wooley et al., 1990; Stein-Behrens et al., 1994; Mararinos et al., 1996). These and other studies confirm that stress induced brain atrophy, loss of neurons and reduced neurogenesis in the hippocampus, may contribute to the pathophysiology of depression (Watanbe et al., 1982; Sapolsky et al., 1985; Uno et al., 1989; Wooley et al., 1990; Stein-Behrens et al., 1994; Elkis et al., 1995; Magarinos et al., 1996).
More recently, the role of pro-inflammatory cytokines in the pathopysiology of depression and related psychiatric disorders has been described. Pro-inflammatory cytokines have been shown to activate the HPA axis and innate immune system in depressed patients (Schiepers et al., 2005). Additionally patients with immune disorders have been shown to exhibit a higher incidence of depression (Dunn et al., 2005). Changes in cytokine profiles have also been demonstrated in depressed patients (Kim et al., 2007; Brambilla et al., 2004). In a clinical study, plasma taken from obsessive compulsive disorder (OCD) patients demonstrated higher levels of the pro-inflammatory cytokines tumor necrosis actor-alpha (TNFα) and interleukin-6 (IL-6) compared with healthy control patients (Konuk et al., 2007). Likewise, rodent models of depression also demonstrate elevation of pro-inflammatory cytokines. In particular, Interleukin-1 (IL-1) has been identified as a key mediator in stress induced depression in these models (Goshen et al., 2008; Koo and Duman., 2007). Evidence that IL-1 exerts an anti-neurogenic effect in these models provides further evidence to support the role of the inflammatory response in psychiatric disorders (Ben Menachem-Zidon et al., 2008).
Chronic anti-depressant treatment with selective serotonin re-uptake inhibitor drugs (SSRIs) has been reported to increase cell proliferation, granule cell survival and to reverse the detrimental effect of stress on hippocampal neurogenesis (Malberg et al., 2000; Malberg and Duman, 2003).
Current therapies for the treatment of psychiatric disorders such as depression and OCD, although efficacious in some patients, require long term, chronic treatment before therapeutic benefit is felt. Unwanted side effects, related to all classes of anti-depressant drugs, can be intolerable and in some patients depressive symptoms may actually become more severe with treatment. Many pharmacological agents are available for the treatment of depression however these are not without their limitations in both efficacy and tolerability.
Three major problems are commonly associated with typical anti-depressant treatments. First there is a large population of patients that do not respond to conventional drug therapy (Stahl et al., 2001). Second, patients experience a long latency period before gaining any therapeutic benefit (Gumnick et al). Lastly, most anti-depressants have a wide range of unwanted side-effects that are related to modulation of brain neurotransmitters and their specific receptors subtypes (Ereshefsky et al., 1997).
Therefore, there exists a need for improved treatments for psychotic disorders that are safe, efficacious and have limited side-effects.